Since 1988 the NIMH Genetics Initiative has supported a national resource for the study of bipolar disorder (BP). This extension of the national genetic resource will include a sample of 5000 unrelated BP probands and 2000 parents for case-control, and family-based association studies. Control samples will be obtained through the NIMH Genetics Initiative national resource. Probands and parents will be ascertained and assessed at eleven sites (the ten sites previously participating plus Howard University, which will provide African-American probands). Parental DNAs in a subsample will allow control for ethnic stratification. This sample will be a national resource for fine scale linkage disequilibrium mapping within regions of linkage, as well as genetic association studies.[unreadable] [unreadable] Previously, we carried out the first genome-wide genetic association study of bipolar disorder, using over 550,000 single nucleotide markers and cases drawn from this collection, as well as controls collected by the NIMH Genetics Initiative, along with a set of cases and controls collected by collaborators in Germany. [unreadable] [unreadable] A major related project, known as the Bipolar Disorder Phenome Project, aims to collate all of the clinical data collected from all 4000+ participants in the Genetics Initiative study that have been enrolled since 1992. This database was completed released to the scientific community in 2007.[unreadable] [unreadable] Last year, this sample was selected by the Genetic Association Information Network (GAIN)for genotyping using 1 million single nucleotide markers. The genotyping was completed in early 2008 and the data have been released to the scientific community as a resource for genetic studies. [unreadable] [unreadable] A large group of collaborators is analyzing these data. We are focusing on genes that play a role in shaping the clinical picture of bipolar disorder, and response to treatment. We are testing the idea that subtypes of bipolar disorder, defined by differing clinical features, will prove to be a more tractable target for genetic association studies, producing larger effects that can be more easily replicated in independent samples. Key clinical features in this project include polarity at onset, frequency of manic and depressive episodes, and global functioning. We are also exploring variables that might be used to estimate an individual's response to lithium, one of the most effective current treatments for bipolar disorder.